Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
  • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
  • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

• the present invention relates to substituted xanthine derivatives, pharmaceutical compositions containing them and their use in therapy, particularly in the treatment or prevention of conditions having an association with TRPC5 containing ion channels.
• ion channel proteins exist to mediate ion flux across cellular membranes.
• the proper expression and function of ion channel proteins is essential for the maintenance of cell function, and the intracellular communication. Numerous diseases are the result of mis-regulation of membrane potential or aberrant calcium handling. Given the central importance of ion channels in modulating membrane potential and ion flux in cells, identification of agents that can promote or inhibit particular ion channels are of great interest as research tools and as possible therapeutic agents.
• Cation channels such as the transient receptor potential (TRP) cation channel subfamily C, member 5 (TRPC5) modulate the flux of calcium and sodium ions across cellular membranes. Sodium and calcium influx leads to a depolarization of the cell. This increases the probability that voltage-gated ion channels will reach the threshold required for activation. As a result, activation of non-selective cation channels can increase electrical excitability and increase the frequency of voltage-dependent events. Voltage-dependent events include, but are not limited to, neuronal action potentials, cardiac action potentials, smooth muscle contraction, cardiac muscle contraction, and skeletal muscle contraction.
• Non-selective cation channels such as TRPC5
• Calcium influx caused by the activation of non-selective cation channels such as TRPC5 also alters the intracellular free calcium concentration.
• Calcium is a ubiquitous second messenger molecule within the cell and the alterations in intracellular calcium levels have profound effects on signal transduction and gene expression.
• activation of non-selective cation channels such as TRPC5 can lead to changes in gene expression and cellular phenotype.
• Gene expression events include, but are not limited to, production of mRNAs encoding cell surface receptors, ion channels, and kinases. These changes in gene expression can lead to hyperexcitability in that cell.
• TRPC5 forms homomultimeric structures such as tetramers (i.e., TRPC5 homomultimers) and heteromultimeric structures such as tetramers (i.e., TRPC5-TRPC1 heteromultimers).
• TRPC5 when the term TRPC5 is used herein, for example, when identifying a modulator of TRPC5 such as a TRPC5 antagonist, the term TRPC5 is used generically so as to include either or both of a TRPC5 homomultimer or a heteromultimer (e.g. TRPC5-TPRC1 or TRPC5-TRPC4 heteromultimer).
• TRPC5 in the literature include the following: Nature 2008 Jan. 3; 451 (7174):69-72; Mol Pharmacol. 2008 January; 73 (1):42-9; J Biol Chem. 2007 Nov. 16; 282 (46):33868-78; Biochem Biophys Res Commun. 2008 Jan. 11; 365 (2):239-45; J Biol Chem. 2006 Nov. 3; 281 (44):33487-96; Eur J Pharmacol. 2005 Mar. 14; 510 (3):217-22; J Biol Chem. 2006 Feb. 24; 281 (8):4977-82; Biochem Soc Trans. 2007 February; 35 (Pt. 1):101-4; Handb Exp Pharmacol. 2007; (179):109-23; J Biol Chem. 2005 Mar. 25; 280 (12):10997-1006; J Physiol. 2006 Jan. 15; 570 (Pt 2):219-35; and Nat Neurosci. (2003) 6: 837-45.
• Modulating the function of TRPC5 proteins provides a means of modulating calcium homeostasis, sodium homeostasis, membrane polarization, and/or intracellular calcium levels
• compounds that can modulate TRPC5 function are useful in many aspects, including, but not limited to, maintaining calcium homeostasis, modulating intracellular calcium levels, modulating membrane polarization, and treating or preventing diseases, disorders, or conditions associated with calcium and/or sodium homeostasis or dyshomeostasis.
• TRPC5 containing ion channels are for example useful for treating conditions such as a neuropsychiatric disorder, a neurodegenerative disorder, nephropathy, and seizure disorder by modulating the activity of the transient receptor potential cation channel subfamily C, member 5 (TRPC5), which can exist in homomultimeric form as well as heteromultimeric form with other ion channels such as TRPC1 or TRPC3 (i.e. TRPC5-TRPC1 and TRPC1-TRPC3-TRPC5).
• TRPC5-TRPC1 and TRPC1-TRPC3-TRPC5 i.e. TRPC5-TRPC1 and TRPC1-TRPC3-TRPC5
• TRPC5-TRPC1 and TRPC1-TRPC3-TRPC5 i.e. TRPC5-TRPC1 and TRPC1-TRPC3-TRPC5
• the present invention provides novel substituted xanthine derivatives of formula I
• Compounds of the present invention are potent TRPC5-inhibitors. They differ from the structurally closest compounds disclosed in WO 2014/143799 in that the C8-position of the xanthine in the compounds of the present invention is substituted with a 2-pyrazinyl group rather than with a phenyl group.
• the compounds of the present invention modulate the function of TRPC5 by inhibiting a TRPC5-mediated ion flux or by inhibiting the inward current, the outward current, or both currents mediated by TRPC5. They are characterized by a higher potency for inhibition of TRPC5, when compared to the closest prior art compounds in WO 2014/143799.
• the present invention thus provides compounds for use in the treatment of a TRPC5 mediated disorder.
• the present invention further provides methods of treating a TRPC5 mediated disorder in a human subject comprising administering to the subject a compound or composition of a compound of the present invention or a pharmaceutically acceptable salt thereof.
• the invention relates to a method for treating a condition for which reduced TRPC5 activity can reduce the severity of the condition, by administering a TRPC5 antagonist, such as a compound as described herein that inhibits a TRPC5-mediated current and/or a TRPC5-mediated ion flux.
• a TRPC5 antagonist such as a compound as described herein that inhibits a TRPC5-mediated current and/or a TRPC5-mediated ion flux.
• Described herein are compounds, which are TRPC5 antagonists that have a measured 1050 for inhibition of TRPC5 of 5 nanomolar or less.
• the compounds described herein, which are TRPC5 antagonists inhibit one or both of inward and outward TRPC5-mediated currents with an 1050 of 5 nanomolar or less.
• the compounds described herein inhibit at least 95% of a TRPC5-mediated current or a TRPC5-mediated ion flux when administered at 1 micromolar or less.
• the compounds described herein, which are TRPC5 antagonists can be used to inhibit a function of TRPC5, for example a TRPC5-mediated current and/or a TRPC5-mediated ion flux.
• the compounds described herein can be used to inhibit a TRPC5 mediated current in vitro, for example in cells in culture.
• the compounds described herein can be used to inhibit a TRPC5 mediated current in vivo.
• the compounds described herein inhibit both an inward and an outward TRPC5-mediated current.
• TRPC5 ion channels as described herein include homomultimeric and heteromultimeric structures (e.g. homomultimeric TRPC5 and heteromeric TRPC5-TRPC1 or TRPC5-TRPC4).
• TRPC5 antagonists include inhibitors having any combination of the structural and/or functional properties disclosed herein.
• an “effective amount” of, e.g. a TRPC5 antagonist, with respect to the subject methods of inhibition or treatment refers to an amount of the antagonist in a preparation which, when applied as part of a desired dosage regimen brings about a desired clinical or functional result.
• an effective amount of a TRPC5 antagonist for use in the methods of the present invention includes an amount of a TRPC5 antagonist effective to decrease one or more in vitro or in vivo function of a TRPC5 channel.
• Exemplary functions include, but are not limited to, membrane polarization (e.g. an antagonist may promote hyperpolarization of a cell), ion flux, ion concentration in a cell, outward current, and inward current.
• an effective amount is an amount sufficient to inhibit a TRPC5-mediated current and/or an amount sufficient to inhibit TRPC5 mediated ion flux.
• TRPC5 antagonists for use in the methods of the present invention may be characterized according to their activity, or lack of activity, against one or more other ion channels.
• inhibition of a function of such other ion channels is defined similarly.
• inhibition of an ion channel or an activity of an ion channel means the antagonist inhibits one or more functional activities of the other ion channel.
• Such functions include the current mediated by the particular ion channel, ion flux, or membrane polarization.
• the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
• Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis.
• An example method includes fractional recrystallizaion using a “chiral resolving acid” which is an optically active, salt-forming organic acid.
• Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ⁇ -camphorsulfonic acid.
• resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of ⁇ -methylbenzylamine (e.g., S- and R-forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, and 1,2-diaminocyclohexane.
• Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
• an optically active resolving agent e.g., dinitrobenzoylphenylglycine
• Suitable elution solvent composition can be determined by one skilled in the art.
• Compounds of the invention also include tautomeric forms, such as keto-enol tautomers.
• a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereoisomers, E/Z isomers) and racemates thereof, as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereoisomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist.
• Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
• the compound of the invention may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H) or carbon-14 ( 14 C). All isotopic variations, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
• “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound forms a salt with an acid or a base.
• acids forming a pharmaceutically acceptable salt with a parent compound containing a basic moiety include mineral or organic acids such as benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid or tartaric acid.
• mineral or organic acids such as benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfur
• salts of amino acids such as arginate
• salts of organic acids like glucuronic or galactunoric acids
• the neutral form of the compounds of the invention is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
• the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
• TRPC5 includes homomultimeric structures (e.g. homomultimeric TRPC5) and heteromultimeric structures (e.g. heteromultimeric TRPC5-TRPC1).
• the biological activity of compounds is determined by the following methods:
• Patch clamp experiments permit the detection of currents through the TRPC5 channel in a cell line.
• a glass electrode is brought into contact with a single cell and a high-resistance (gigaohm) seal is established with the cell membrane.
• the membrane is then ruptured to achieve the whole-cell configuration, permitting control of the voltage of the cell membrane and measurement of currents flowing across the membrane using the amplifier attached to the electrode and resulting in the replacement of cytoplasm with the pipette solution.
• a perfusion system permits control of the extracellular solution, including the addition of blockers and activators of the current.
• the current can be activated by including 1.4 ⁇ M free Ca2+ in the pipette (intracellular) solution, and 80 ⁇ M LaCl 3 in the extracellular solution.
• TRPC5 cells were induced 20-48 hours, removed from growth plates, and replated at low density (to attain good single-cell physical separation) on glass coverslips for measurement. In some cases, cells were grown in low density overnight on glass coverslips. Patch clamp recordings were made in the whole-cell mode with a holding potential of ⁇ 40 mV. Every 5 seconds, a voltage ramp was applied from ⁇ 120 to +100 mV, 400 ms in duration. Currents elicited were quantified at ⁇ 80 mV and +80 mV.
• the internal solution consisted of 140 mM cesium aspartate, 10 mM HEDTA, 2 mM CaCl 2 , 2.27 mM MgCl 2 and 10 mM HEPES, pH 7.2, with 1,400 nM calculated free Ca2+.
• the external solution consisted of 150 mM NaCl, 4.5 mM 15 KCl, 1 mM MgCl 2 , 2 mM CaCl 2 , 10 mM HEPES, 10 mM glucose, 1 mM EGTA, pH 7.4.
• TRPC5 current was induced only in TRPC5-expressing cells and not in parental HEK293 TREx cells. Removal of the LaCh stimulus causes most of the current to go away. Potential blockers were tested for ability to block both inward and outward currents in the continued presence of LaCl 3 .
• IC50 of a compound of the invention was estimated by testing the compound 500 nM. When 500 nM of a compound showed no block, 1050 was estimated as >1 ⁇ M. Compounds blocking 50% or more at 500 nM are retested at multiple concentrations, and the % block is fitted by standard equations to determine 1050 accurately, using a 5 ⁇ 6 point concentration-response experiment.
• the compounds of the present invention differ structurally from Examples 441 and 465 in WO 2014/143799, i.e. the closest prior art compounds, in that the C8-position of the xanthine in the presently claimed compounds is substituted with a 2-pyrazinyl rather than with a phenyl group as in Examples 441 and 465 of WO 2014/143799. Furthermore, the heteroaryl group in the presently claimed compounds is substituted with a cycloalkyl-O— group rather than with a methoxy-group, as in Examples 441 and 465 of WO 2014/143799. These structural differences unexpectedly result in a markedly increased potency in TRPC5-inhibition. (Tables 1 and 2).
• the present invention is directed to compounds which are useful in the treatment of a disease, disorder and condition wherein the inhibition of the activity of the transient receptor potential cation channel TRPC5 is of therapeutic benefit.
• This includes but is not limited to the treatment and/or prevention of psychiatric, neurological or neurodegenerative conditions, pain, seizure, non-neuronal conditions, and cancer.
• Psychiatric conditions include diseases associated with dysregulated emotional processing (e.g. borderline personality disorder or depressive disorders like major depression, major depressive disorder, psychiatric depression, dysthymia, and postpartum depression, and bipolar disorders), anxiety and fear-related disorders (e.g. post-traumatic stress disorder, panic disorder, agoraphobia, social phobias, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive compulsive disorder, and separation anxiety), memory disorders (e.g.
• dysregulated emotional processing e.g. borderline personality disorder or depressive disorders like major depression, major depressive disorder, psychiatric depression, dysthymia, and postpartum depression, and bipolar disorders
• anxiety and fear-related disorders e.g. post-traumatic stress disorder, panic disorder, agoraphobia, social phobias, generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive compulsive disorder, and separation anxiety
• memory disorders e.g.
• Alzheimer's disease amnesia, aphasia, brain injury, brain tumor, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia, fugue amnesia, Huntington's disease, learning disorders, sleeping disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke, and Wernicke-Korsakoff syndrome), disorders associated with impaired impulse control and addiction.
• Neurological or neurodegenerative conditions include e.g. Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and other brain disorders caused by trauma or other insults including aging.
• AD Alzheimer's disease
• Parkinson's disease Parkinson's disease
• Huntington's disease Huntington's disease
• amyotrophic lateral sclerosis ALS
• other brain disorders caused by trauma or other insults including aging.
• Pain disorders include nociceptive pain, inflammatory pain, cancer pain, and neuropathic pain (e.g. cancer pain, osteoarthritic pain, rheumatoid arthritis pain, post-herpetic neuralgia, pain due to burns, and other indications).
• the pain can be chronic or acute.
• Seizures may be induced by excitotoxicity of a variety of origins. Commonly excess neuronal firing can drive seizure activity. Compounds that reduce the hyperexcitability of relevant neuronal populations have significant potential in reducing seizure activity. Compounds of the invention that inhibit TRPC5 may reduce hyperexcitability and thus reduce seizure activity.
• Non-neuronal conditions include nephropathy, proteinuric kidney disease, liver diseases such as hepatic dyslipidemia associated with cholestasis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) [WO2018/146485], itch, disorders associated with malfunction of the cardiovascular-vascular system or vascular permeability (e.g. pulmonary arterial hypertension, acute respiratory distress syndrome (ARDS), maladaptive cardiac remodeling, disorders associated with maladaptive blood pressure control like hypertension or hypotension, and other medical conditions such as diabetes, insulin resistance, metabolic syndrome and obesity. It is envisaged that the use for treatment of non-neuronal conditions may also extend to the use for cosmetic weight loss (WO2018/146485).
• compositions for use in a human patient comprising an effective amount of a compound described herein (or a pharmaceutically acceptable salt thereof), and one or more pharmaceutically acceptable excipient(s).
• the invention further contemplates the use of the compounds described herein in the manufacture of a medicament or a pharmaceutical composition to treat or reduce the symptoms of any of the diseases or conditions provided in the specification.
• the compounds described herein can be used for treating a particular disease or condition and can be formulated for administration via a route appropriate for the particular disease or condition.
• the applicable daily dose of compounds of the present invention may vary from 0.1 to 2000 mg.
• the actual pharmaceutically effective amount or therapeutic dose will depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease.
• the drug substance is to be administered at a dose and in a manner which allows a pharmaceutically effective amount to be delivered that is appropriate to the patient's condition.
• compositions for administering the compounds of the present invention will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives, and powders.
• the content of the pharmaceutically active compound(s) may vary in the range from 0.1 to 95 wt.-%, preferably 5.0 to 90 wt.-% of the composition as a whole.
• Suitable tablets may be obtained, for example, by mixing a compound of the present invention with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants and compressing the resulting mixture to tablets.
• excipients for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants
• the compounds of the present invention can be used alone or in combination with other active pharmaceutical ingredients.
• compounds according to the present invention can be combined with other treatment options known to be used in the art in connection with a treatment of any of the indications the treatment of which is in the focus of the present invention.
• active pharmaceutical ingredients or treatment options that are considered suitable for combination with the compounds and the treatment according to the present invention are antidepressants, mood stabilizers, typical and atypical antipsychotics, anxiolytics, antiepileptic drugs, sleeping agents, cognitive enhancers, stimulants, additional psychoactive drugs, anti-inflammatory drugs, analgesic drugs, chemotherapeutic drugs as well as active pharmaceutical ingredients used or potentially useful in the treatment of metabolic disorders, liver diseases and kidney diseases, the latter active pharmaceutical ingredients also including potential inhibitors of TRPC3 and/or TRPC6.
• HPLC-Methods Method Name: A Column: XBridge BEH C18_2.1 ⁇ 30 mm, 1.7 ⁇ m Column Supplier: Waters Gradient/ % Sol Solvent [H 2 O, % Sol Flow Temp Time [min] 0.1% TFA] [ACN] [mL/min] [° C.] 0.00 99 1 1.6 60 0.02 99 1 1.6 60 1.00 0 100 1.6 60 1.10 0 100 1.6 60
• NMR method NMR spectra were recorded on a Bruker AVANCE IIIHD 400 MHz instrument using TopSpin 3.2 pI6 software. Chemical shifts are given in parts per million (ppm) downfield from internal reference trimethylsilane in ⁇ units. Selected data are reported in the following manner: chemical shift (multiplicity, coupling constants (J), number of hydrogens). Abbreviations are as follows: s (singulet), d (doublet), t (triplet), q (quartet), spt (septet), m (multiplet), br (broad).
• Intermediate 4.2 was prepared in an analogous manner to intermediate 4.1 using intermediate 3.1 and 5-bromo-3-methylpyrazine-2-carbaldehyde.
• Intermediate 6.2 was prepared in an analogous manner to intermediate 6.1 using intermediate 5.2 (1 h, 80° C.).
• Example 4 was prepared in an analogous manner to example 3 using intermediate 6.4.
• Example 6 was prepared in an analogous manner to example 5 using intermediate 6.6.

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